Septic shock as a consequence of Gram-negative bacteremia or endotoxemia remains a critical clinical condition in spite of adequate antibiotic therapy.
It is now known that the lethal consequences of septic shock results from an exaggerated host response, mediated by protein factors such as TNF and interleukin 1 (IL-1), rather than from the pathogen directly.
Tumour necrosis factor (TNF) is a cytokine produced mainly by activated macrophages, which elicits a wide range of biological effects. These include an important role in endotoxic shock and in inflammatory, immunoregulatory, proliferative, cytotoxic and anti-viral activities.
The induction of the various cellular responses mediated by TNF is initiated by its interaction with two distinct cell surface receptors of approximately 55 kDA (also called TNF-R1) and 75 kDA (also called TNF-R2). The extracellular soluble portions of these receptors, called respectively TBP-I (TNF Binding Protein-1) and (TBP-2 (TNF Binding Protein-2), have been isolated and cloned (see EP patents 308 378, 398 327 and U.S. Pat. No. 5,811,261).
Several studies in animal models of TNF-mediated endotoxic shock indicated that both anti-TNF antibodies and soluble TNF-receptor are able to counteract the lethal effects induced (see for example: Bentler, B et al., Science, 229:869 (1985), Lesslauer, W. et al. Eur. J. Immunol. 21:2883 (1991). Evans. T. J. et al. J. Exp. Med. 180:2173 (1994) and Mohler K. M. et al. J. Immunol. 151:1548 (1993)).
The in vivo protective effects of urinary as well as recombinant TBP-1 (derived from both CHO and E. Coli cells) in experimental models of septic shock have already been demonstrated (see Bertini. R. et al. Eur. Cytokine Netw. 4(1):39 (1993) and Ythier A., et al. Cytokines. 5:459 (1993)).
DHEA (INN: Prasterone) is an adrenocortical steroid hormone which is an intermediate in the biosynthesis of other hormones including testosterone and estradiol-17β.
The precise biological functions of DHEA are still unclear. Experimental and epidemiological data suggest an inverse relationship between low levels of DHEA in serum and morbidity from atherosclerotic cardiovascular disease (see Barret-Connor. D. et al. N. Engl. J. Med. 315:1519 (1986)), cancer (see Gordon. G. B., et al., Cancer Res. 51:1366 (1991)) and immunodeficiency virus (HIV) infection (Villette. J M. et al J. Clin. Endocrinol. Metab. 70:57 (1990)).
An immunomodulating activity of this drug has also been reported; in particular, DHEA has been shown to prevent the development of systemic lupus erythematosus in a mouse model (Lucas. J. et al. J. Clin. Invest. 75:2091 (1985)).
It has been demonstrated that DHEA regulates the systemic resistance against lethal viral infections induced by different viruses: coxsackievirus B4 (as reported in Loria. R. M. et al. Ann. N.Y. Acad. Sci. 293), herpes virus type 2 (see Loria. R. M. et al. J. Med. Virol., 26:301 (1988)), West Nile virus (a neurovirulent Sindbis virus) and Semliki Forest virus (as reported in Ben-Nathan, D. et al. Arch. Virol. 20:263 (1989)).
It has also been reported that DHEA has similar protective effects against a lethal bacterial infection induced by Enterococcus faecalis (see Loria, R. M. et al. in Symposium Pharmaco-Clinique. Roussel-Uclaf 9:24 (1989)).
Danenberg. H. D. et at. (Antimicrob. Agents Chemother. 36:2275 (1992)) reported that DHEA has the capability of protecting mice from septic shock induced by lipopolysaccharides (LPS) alone or by Tumor Necrosis Factor alpha (TNF-α) in combination with D-Galactosamine. LPS administration resulted in high levels of TNF-α, a response that was significantly blocked by DHEA, both in vivo and in vitro.